This research program is investigating questions concerning immune responses elicited by viral and plasmid vectors, with a focus on mechanisms of protective immunity to influenza virus infection. Main projects: a) Heterosubtypic immunity: Protection against influenza A virus challenge is induced in animals by prior infection with a virus subtype differing from the challenge virus, but it is not known what immune mechanism is responsible. Our experiments have shown that neither CD4+ nor CD8+ T cells are required at the time of challenge, and that passive antibody does not transfer such immunity. Additional mechanisms are under investigation. b) Vaccination with plasmid DNA: Plasmid DNA is under study as a new type of vaccine and also as a new type of gene therapy vector; such products are in clinical trials. We are effects of plasmids encoding influenza virus antigens. Mechanisms of protection are being analyzed. Potency and specificity of immunity have not been adequately examined in previous studies, and we are performing validation studies in this area. c) Immunization of beta2-microglobulin deficient mice. These mice were shown to make lower than normal antibody responses for reasons that are unclear. We are further investigating the basis for this defect. Analysis of this question will help us understand efficacy of licensed vaccines in immunodeficient individuals. d) Protective immunity in mice with selective immune deficiencies. Strains of knock-out mice lacking all antibodies, or selectively lacking particular antibodies, are being studied for ability to survive influenza, either as a primary infection or a challenge following immunization.